Abstract
p38 mitogen-activated protein kinase (MAPK) signal transduction pathways are essential regulators of the immune response. Particularly, p38γ and p38δ regulate many immune cell functions such as cytokine production, migration, or T cell activation; however, their involvement in immune cell development is largely unknown. Here, we analysed the role of p38 MAPK isoforms p38γ and p38δ in T cell differentiation in the thymus and in lymph nodes, using mice deficient in p38γ, p38δ, or in both. We found that the T cell differentiation program in the thymus was affected at different stages in p38γ-, p38δ-, and p38γ/δ-deficient mice, and also peripheral T cell homaeostasis was compromised. Particularly, p38δ deletion affects different stages of early CD4−CD8− double-negative thymocyte development, whereas lack of p38γ favours thymocyte positive selection from CD4+CD8+ double-positive to CD4+ or CD8+ single-positive cells. Our results identify unreported functions for p38γ and p38δ in T cells.
Highlights
In the thymus, the development of T cell from CD4−CD8− double-negative (DN) to CD4+CD8+ double-positive (DP) and into CD8+ or CD4+ single-positive (SP) cells is regulated by multiple signalling pathways that induce cell-specific gene expression [1, 2]
We examined the mRNA and protein expression of the four p38 mitogen-activated protein kinase (MAPK) isoforms in isolated thymocytes and observed that all p38 MAPKs were expressed in WT T cells, whereas p38γ was not expressed in p38γ−/− and p38γ/δ−/− T cells, and p38δ was not expressed in p38δ−/− and p38γ/δ−/− T cells (Figures 1A,B)
Total thymocyte cellularity and the absolute numbers of DN, DP, and SP CD4+ and CD8+ thymocytes were reduced in p38γ−/−, p38δ−/−, and p38γ/δ−/− mice compared with WT mice; this reduction was more evident in p38γ/δ−/− mice than in the other genotypes
Summary
The development of T cell from CD4−CD8− double-negative (DN) to CD4+CD8+ double-positive (DP) and into CD8+ or CD4+ single-positive (SP) cells (a process known as positive selection) is regulated by multiple signalling pathways that induce cell-specific gene expression [1, 2]. The mitogen-activated protein kinase (MAPK) signalling pathways, including extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, have been implicated in thymocyte differentiation [3,4,5]. Of these three major MAPK pathways, the ERK pathway is known to be involved in T cell positive selection [6,7,8], since ERK1-deficient mice exhibit defects in T cell maturation [9]. Using mice deficient in p38γ, p38δ, or both, it has been shown that these kinases are crucial for the inflammation and the innate immune response, by controlling immune cell response
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